My previous articles on LDN discuss its use in Multiple Sclerosis (1,2) and Crohn’s Disease (3,4). This article deals with the use of LDN for Chronic Pain Syndromes of Fibromyalgia and Reflex Sympathetic Dystrophy, RSD.

Reflex Sympathetic Dystrophy, RSD, is a neurological disorder in which a minor injury to an extremity leads to a chronic and debilitating pain syndrome called Allodynia, a form of hypersensitivity to touch. Any minor brushing or touching the skin triggers a severely painful sensation which may in turn trigger muscle spasms. The sensory-motor feedback loop in the spinal cord is magnified. Typically, there is also disturbance of the sympathetic nervous system with increased vascular flow, discoloration and swelling of the extremity.

RSD Case Report

I recall one young female who had RSD of the leg. Many years ago, her leg had been struck by a car while she was a pedestrian. The injury was minor and she recovered quickly. However, there was residual neurologic damage. She had “allodynia”, severe pain would result from a light touch to the skin, and the leg immediately went into muscle spasms. Any minimal sensory input was magnified in a feedback loop to the motor neurons system which caused excessive uncontrollable muscle movements and spasms. She had been to numerous doctors, clinics, rehabilitation facilities, and nothing they did could halt the progression of the symptoms. The doctors had given her various psychoactive drugs and increasing doses of narcotic pain killers, providing some temporary relief, yet none was effective long term. She was now confined to a wheel chair and addicted to narcotics. Her future appeared bleak. However she had not yet been treated with LDN, and this was worth a try.

Low Dose Naltrexone is a capsule taken at night before sleep. Except for the fact that it is a narcotics blocker, there are no known adverse effects. Habitual users of narcotic pain pills (oxycodone, morphine, tramadol) will be thrown into drug withdrawal if they take LDN, so it is not advised for this group.

Radionuclide Bones Scans

Decades ago when I was a nuclear medicine resident in training, we did radionuclide bone scans on the RSD patients. The diagnosis was made by increased uptake in the affected extremity (left image).(16-18)

As was usual in those days, diagnosis was way ahead of treatment for these disorders. Medical science had little to offer the RSD patient. If you can’t cure it, then the next best thing is to rename it. RSD has now been renamed “Complex Regional Pain Syndrome”.

This is exactly why I found reports of successful outcomes using LDN for RDS so intriguing. RSD patients drag themselves from clinic to clinic having no effective treatment for the relentless progression of disease. They have little to offer except chronic narcotic addiction which is actually worse than the underlying disease.

Fibromyalgia Related to RSD

A number of studies and anecdotal reports show that LDN is useful for the fibromyalgia patient. (8-15) Perhaps Fibromyalgia and Chronic Regional Pain Syndrome are related in some way, since LDN seems to be effective for fibromyalgia as well. Perhaps the common thread is microglia activation in the central nervous system. LDN is an anti-inflammatory agent in the central nervous system, via action on microglial cells. (5)

According to Pradeep Chopra, MD ” In painful conditions such as Complex regional pain) and neuropathic pain, damage to the peripheral nerves shifts the glia to an activated state within the spinal cord….Glia are activated by trauma, injury, infection, opioids. When activated, glia release pro-inflammatory and neurotoxic factors (cytokines)….Drugs that block the effect of opioids (morphine) may help prevent activation of glia. Such drugs are naltrexone and naloxone. Low dose naltrexone (hence, LDN) may inhibit the activation of glia.”(6)

Nancy Sajben MD comments: ” New science shows naltrexone to be a potent anti-inflammatory — much stronger and with a much different mechanism than the weaker cox inhibitors such as ibuprofen, Vioxx, Celebrex, Naproxen with none of those adverse side effects. Dr. Hong reports that in animal studies, dextromethorphan is even stronger than naltrexone.”(20)

Chronic Major Depression – LDN Effective

Nancy Sajben MD suggests the anti-inflammatory activity of LDN explains its effectiveness in Major Depression refractory to the usual medications such as SSRI drugs. (19-20)

Another treatment modality showing success against RSD chronic refractory pain is medicinal marijuana.(21) “An oral cannabinoid was associated with up to 60% reductions in pain in 10 patients with refractory complex regional pain syndrome (CRPS), according to research presented at the 2010 annual World Congress on Pain in Montreal. The study investigators also reported that most of the patients were able to discontinue long-term opioid therapy and reported signi ficant improvements in quality of life.” (21) from Pharmacy Practice News. (More on this report)

Cannabis for Fibromyalgia Pain – works better than prescription medications. “Medical marijuana is far more effective at treating symptoms of fibromyalgia than any of the three prescription drugs Cymbalta, Lyrica and Savella” (22)

Cannabis for Chronic Pain (23-25)

Current treatment of chronic pain leaved much to be desired. Chronic opiate use is not a good long term solution, yet is commonly employed. Studies show that in chronic patients on long term opiates, they report an augmented reduction in pain when vaporized cannabis is inhaled (25) Cannabis has been suggested as an adjunct or substitute for opiates in the treatment of chronic pain. This is our goal, to wean patients off addictive and dangerous opiates to safer alternatives. Any day a chronic pain patient can be weaned off opiates, that a good day.

Clin Rheumatol. 2014 Feb 15. [Epub ahead of print]
The use of low-dose naltrexone (LDN) as a novel anti-inflammatory treatment for chronic pain. Younger J1, Parkitny L, McLain D.
Low-dose naltrexone (LDN) has been demonstrated to reduce symptom severity in conditions such as fibromyalgia, Crohn’s disease, multiple sclerosis, and complex regional pain syndrome. We review the evidence that LDN may operate as a novel anti-inflammatory agent in the central nervous system, via action on microglial cells. These effects may be unique to low dosages of naltrexone and appear to be entirely independent from naltrexone’s better-known activity on opioid receptors. As a daily oral therapy, LDN is inexpensive and well-tolerated. Despite initial promise of efficacy, the use of LDN for chronic disorders is still highly experimental. Published trials have low sample sizes, and few replications have been performed. We cover the typical usage of LDN in clinical trials, caveats to using the medication, and recommendations for future research and clinical work. LDN may represent one of the first glial cell modulators to be used for the management of chronic pain disorders.

In painful conditions such as Complex regional pain) and neuropathic pain, damage to the peripheral nerves shifts the glia to an activated state within the spinal cord. Glia are activated by trauma, injury, infection, opioids. When activated, glia release pro-inflammatory and neurotoxic factors (cytokines).
Drugs that block the effect of opioids (morphine) may help prevent activation of glia. Such drugs are naltrexone and naloxone. Low dose naltrexone (hence, LDN) may inhibit the activation of glia.

RESULTS:When contrasting the condition end points, we observed a significantly greater reduction of baseline pain in those taking low-dose naltrexone than in those taking placebo (28.8% reduction versus 18.0% reduction; P = 0.016). Low-dose naltrexone was also associated with improved general satisfaction with life (P = 0.045) and with improved mood (P = 0.039), but not improved fatigue or sleep. Thirty-two percent of participants met the criteria for response (defined as a significant reduction in pain plus a significant reduction in either fatigue or sleep problems) during low-dose naltrexone therapy, as contrasted with an 11% response rate during placebo therapy (P = 0.05). Low-dose naltrexone was rated equally tolerable as placebo, and no serious side effects were reported.
CONCLUSION:The preliminary evidence continues to show that low-dose naltrexone has a specific and clinically beneficial impact on fibromyalgia pain. The medication is widely available, inexpensive, safe, and well-tolerated. Parallel-group randomized controlled trials are needed to fully determine the efficacy of the medication.

Fibromyalgia is a chronic pain disorder that is characterized by diffuse musculoskeletal pain and sensitivity to mechanical stimulation. In this pilot clinical trial, we tested the effectiveness of low-dose naltrexone in treating the symptoms of fibromyalgia. Participants completed a single-blind, crossover trial with the following time line: baseline (2 weeks), placebo (2 weeks), drug (8 weeks), and washout (2 weeks).
PATIENTS:Ten women meeting criteria for fibromyalgia and not taking an opioid medication.
INTERVENTIONS:Naltrexone, in addition to antagonizing opioid receptors on neurons, also inhibits microglia activity in the central nervous system. At low doses (4.5 mg), naltrexone may inhibit the activity of microglia and reverse central and peripheral inflammation.
OUTCOME MEASURES:Participants completed reports of symptom severity everyday, using a handheld computer. In addition, participants visited the lab every 2 weeks for tests of mechanical, heat, and cold pain sensitivity.
RESULTS:Low-dose naltrexone reduced fibromyalgia symptoms in the entire cohort, with a greater than 30% reduction of symptoms over placebo. In addition, laboratory visits showed that mechanical and heat pain thresholds were improved by the drug. Side effects (including insomnia and vivid dreams) were rare, and described as minor and transient. Baseline erythrocyte sedimentation rate predicted over 80% of the variance in drug response. Individuals with higher sedimentation rates (indicating general inflammatory processes) had the greatest reduction of symptoms in response to low-dose naltrexone.
CONCLUSIONS:We conclude that low-dose naltrexone may be an effective, highly tolerable, and inexpensive treatment for fibromyalgia.

14)http://www.amazon.com/forum/fibromyalgia/Tx21ZZRT64Y2YG0
Ms. Linda G. Zambanini says: I am an RN and Information Scientist who researches novel adjuvant cancer therapies and i had fibromyalgia. I say HAD because i no longer have fibromyalgia pain. I was in horrible pain for 8 years prior to that. I initially learned about LDN as a novel adjuvant for cancer – but soon learned it was also being used for fibromyalgia. I have been on Low Dose Naltrexone (also called LDN) for over a year now and the results have been nothing short of miraculous. It is an old, off-patent drug that is compounded and used in dosages less than a 1/10th of the original dosage. As such it functions as an immunomodulator. That is, if one’s immune system is hyperactive as with autoimmune diseases like SLE and MS it brings it down to normal; and if one’s immune system is hypoactive as with cancer and HIV it brings it up to normal. LDN is currently being being studied for fibromyalgia at Stanford; but only after getting funding from the Fibromyalgia Society since drug companies were not interested (in fact they are not interested in it for cancer or MS or any other indication) – it is an old off patent drug which one can buy for almost nothing. (I get 3 months worth from a compounding pharmacy in Colorado -Belmar Pharmacy – for about $40). From the research i had done prior to taking it most reported it took several months for it to work in the case of fibromyalgia (much faster results with MS). Sure enough it did not work for me initially, but knowing what to expect i continued it and after 2 months i became painfree! It had been so long since i had been pain free i had almost forgotten what that was like. I hope everyone with fibromyalgia looks into LDN. In fact if you know anyone with Cancer, SLE, Crohns disease, MS, HIV etc… please let them know about LDN. There are many videos on Youtube about LDN also. Just type LDN or low dose naltrexone in the search box.www.lowdosenaltrexone.orghttp://snapl.stanford.edu/ldn/

Reflex sympathetic dystrophy syndrome (RSDS) is a painful and disabling problem, the diagnosis of which can be difficult to confirm by objective measures. The three-phase technetium bone scan (TPBS), with a combined sensitivity and specificity of greater than 90%, has been recommended for use in the diagnosis of RSDS. The purpose of this study was to determine the predictive value and usefulness of the TPBS in the diagnosis of RSDS and to discover how the predictive value might be influenced by demographic and medical factors (eg, duration of symptoms). A retrospective chart review was conducted of 119 patients who underwent a TPBS as part of a workup for unexplained limb pain. Twenty-five patients met the Kozin criteria for definite or probable RSDS. All patients were injected with technetium-99m methylene diphosphonate and scanned using established criteria. The three-hour delayed image demonstrated a sensitivity of 44%, a specificity of 92%, a positive predictive value of 61%, and a negative predictive value of 86%. The blood-flow and pool-imaging phases added no further sensitivity or specificity to that achieved by the uptake scan in patients with upper-extremity involvement. Blood-flow and pool-imaging did improve the predictive value of the TPBS in patients with involvement of the lower extremities. We conclude that a more cost-effective approach to diagnosis of upper-extremity RSDS is to use the uptake scan alone.

New science shows naltrexone to be a potent anti-inflammatory — much stronger and with a much different mechanism than the weaker cox inhibitors such as ibuprofen, Vioxx, Celebrex, Naproxen with none of those adverse side effects. Dr. Hong reports that in animal studies, dextromethorphan is even stronger than naltrexone.

(21) http://www.braatah.com/refractory-crps-patients-discontinue-opiates-with-cannabinoid-treatment/
Refractory CRPS Patients Discontinue Opiates With Cannabinoid Treatment by David Wild, Pharmacy Practice News
Montreal—An oral cannabinoid was associated with up to 60% reductions in pain in 10 patients with refractory complex regional pain syndrome (CRPS), according to research presented at the 2010 annual World Congress on Pain in Montreal. The study investigators also reported that most of the patients were able to discontinue long-term opioid therapy and reported significant improvements in quality of life.

Medical marijuana is far more effective at treating symptoms of fibromyalgia than any of the three prescription drugs approved by the Food and Drug Administration to treat the disorder.

That is one of the surprise findings in an online survey of over 1,300 fibromyalgia patients conducted by the National Pain Foundation and National Pain Report.

Cymbalta graphThe FDA has approved only three drugs – Cymbalta, Lyrica and Savella — for the treatment of fibromyalgia. Although they generate billions of dollars in annual sales for Pfizer, Eli Lilly, Forest Laboratories and other drug makers, most who have tried the medications say they don’t work.

Fifteen of the eighteen trials that met the inclusion criteria demonstrated a significant analgesic effect of cannabinoid as compared with placebo and several reported significant improvements in sleep. There were no serious adverse effects. Adverse effects most commonly reported were generally well tolerated, mild to moderate in severity and led to withdrawal from the studies in only a few cases. Overall there is evidence that cannabinoids are safe and modestly effective in neuropathic pain with preliminary evidence of efficacy in fibromyalgia and rheumatoid arthritis.

25) http://www.ncbi.nlm.nih.gov/pubmed/22048225
Clin Pharmacol Ther. 2011 Dec;90(6):844-51. doi: 10.1038/clpt.2011.188. Epub 2011 Nov 2.
Cannabinoid-opioid interaction in chronic pain.
Abrams DI1, Couey P, Shade SB, Kelly ME, Benowitz NL.
Cannabinoids and opioids share several pharmacologic properties and may act synergistically. The potential pharmacokinetics and the safety of the combination in humans are unknown. We therefore undertook a study to answer these questions. Twenty-one individuals with chronic pain, on a regimen of twice-daily doses of sustained-release morphine or oxycodone were enrolled in the study and admitted for a 5-day inpatient stay. Participants were asked to inhale vaporized cannabis in the evening of day 1, three times a day on days 2-4, and in the morning of day 5. Blood sampling was performed at 12-h intervals on days 1 and 5. The extent of chronic pain was also assessed daily. Pharmacokinetic investigations revealed no significant change in the area under the plasma concentration-time curves for either morphine or oxycodone after exposure to cannabis. Pain was significantly decreased (average 27%, 95% confidence interval (CI) 9, 46) after the addition of vaporized cannabis. We therefore concluded that vaporized cannabis augments the analgesic effects of opioids without significantly altering plasma opioid levels. The combination may allow for opioid treatment at lower doses with fewer side effects.

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Russo EB

http://www.ncbi.nlm.nih.gov/pubmed/18728714
Ther Clin Risk Manag. 2008 Feb;4(1):245-59.
Cannabinoids in the management of difficult to treat pain.
Russo EB. GW Pharmaceuticals Vashon, WA, USA.
This article reviews recent research on cannabinoid analgesia via the endocannabinoid system and non-receptor mechanisms, as well as randomized clinical trials employing cannabinoids in pain treatment. Tetrahydrocannabinol (THC, Marinol((R))) and nabilone (Cesamet((R))) are currently approved in the United States and other countries, but not for pain indications. Other synthetic cannabinoids, such as ajulemic acid, are in development. Crude herbal cannabis remains illegal in most jurisdictions but is also under investigation. Sativex((R)), a cannabis derived oromucosal spray containing equal proportions of THC (partial CB(1) receptor agonist ) and cannabidiol (CBD, a non-euphoriant, anti-inflammatory analgesic with CB(1) receptor antagonist and endocannabinoid modulating effects) was approved in Canada in 2005 for treatment of central neuropathic pain in multiple sclerosis, and in 2007 for intractable cancer pain. Numerous randomized clinical trials have demonstrated safety and efficacy for Sativex in central and peripheral neuropathic pain, rheumatoid arthritis and cancer pain. An Investigational New Drug application to conduct advanced clinical trials for cancer pain was approved by the US FDA in January 2006. Cannabinoid analgesics have generally been well tolerated in clinical trials with acceptable adverse event profiles. Their adjunctive addition to the pharmacological armamentarium for treatment of pain shows great promise.

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